Cefepime Monotherapy Research Articles

Ceftriaxone-resistant viridans streptococci bacteraemia among patients treated at a large comprehensive cancer care centre: a retrospective eighteen-year study.

Viridans streptococci (VS) are opportunistic oral commensals and a common cause of bacteraemia in neutropenic patients. In this retrospective single centre cohort study, we investigated the prevalence of ceftriaxone resistance in VS (CRO-R VS) blood isolates between January 2005 and December 2022 from patients treated at a tertiary care hospital. Blood culture isolates were identified using biochemicals and mass spectrometry. Susceptibility testing was performed by Kirby-Bauer and Epsilometer tests. Demographic data, clinical outcomes and antimicrobial use were assessed through electronic medical record review. Among 791 patients with VS bacteraemia, 31 (4%) had confirmed CRO-R VS bacteraemia over the 18-year period; 20/31 (65%) were patients also treated at the Fred Hutchinson Cancer Center and were the focus of this study. Of these 20 patients, 18 (90%) had a known haematologic malignancy; 14 (70%) had undergone haematopoietic cell transplant (HCT); 18 (90%) were neutropenic at the time of culture. Two (10%) patients died within 30 days of CRO-R VS bacteraemia. All the CRO-R isolates (20/20) were members of the Streptococcus mitis group, 12 were multi-drug resistant; all were susceptible to vancomycin. Most patients received vancomycin once blood cultures were positive for a Gram-positive organism. During the study period, the frequency of VS isolate susceptibility testing increased; however, there was no concomitant increase in the percentage of CRO-R isolates at our facility. These data are important in an era where cefepime monotherapy is often used and reinforces the importance of routine resistance testing among VS bacteraemia.

Best Practice of Peritoneal Dialysis-Associated Gram-Negative Peritonitis in Children: Insights From the International Pediatric Peritoneal Dialysis Network Registry

Gram-negative peritonitis (GNP) is associated with significant morbidity in children receiving long-term peritoneal dialysis (PD) and current treatment recommendations are based on limited data. Analysis of 379 GNP episodes in 308 children (median age 6.9 years, interquartile range [IQR]: 3.0-13.6) from 45 centers in 28 countries reported to the International Pediatric Peritoneal Dialysis Network registry between 2011 and2023. Overall, 74% of episodes responded well to empiric therapy and full functional recovery (FFR) was achieved in 82% of cases. Invitro bacterial susceptibility to empiric antibiotics and lack of severe abdominal pain at onset were associated with a good initial response. Risk factors for failure to achieve FFR included severe abdominal pain at onset and at 60 to 72 hours from treatment initiation (odds ratio [OR]: 3.81, 95% confidence interval [CI]: 2.01-7.2 and OR: 3.94, 95% CI: 1.06-14.67, respectively), Pseudomonas spp. etiology (OR: 1.73, 95% CI: 1.71-4.21]) and invitro bacterial resistance to empiric antibiotics (OR: 2.40, 95% CI: 1.21-4.79); the risk was lower with the use of monotherapy as definitive treatment (OR: 0.40, 95% CI: 0.21-0.77). Multivariate analysis showed no benefit of dual antibiotic therapy for treatment of Pseudomonas peritonitis after adjustment for age, presenting symptomatology, 60 to 72-hour treatment response, and treatment duration. Monotherapy with cefazolin in susceptible Enterobacterales peritonitis resulted in a similar FFR rate (91% vs. 93%) as treatment with ceftazidime or cefepime monotherapy. Detailed microbiological assessment, consisting of patient-specific and center-specific antimicrobial susceptibility data, should guide empiric treatment. Treatment "deescalation" with the use of monotherapy and narrow spectrum antibiotics according to susceptibility data is not associated with inferior outcomes and should be advocated in the context of emerging bacterial resistance.

#90: Outcomes of Gram-negative Bacteremia Managed According to a Risk-based Algorithm

Abstract Background Management of gram-negative bacteremia (GNB) in children with cancer (CWC) is complicated by increasing rates of antimicrobial resistance. Guidelines for the management of CWC with suspected serious bacterial infections at St. Jude Children’s Research Hospital (SJ) recommend cefepime (CEF) monotherapy for empirical therapy for most patients. Children with evidence of sepsis, recent treatment with CEF or known colonization with a CEF-resistant (CEF-R) organism are initially treated with meropenem and/or amikacin. We compared outcomes of CWC with infections caused by CEF susceptible (CEF-S) and CEF-R bacteria treated according to this algorithm. Methods Demographic information on patients, and clinical and microbiological characteristics of 100 episodes of GNB treated from May 2018 to April 2019 at SJ were retrospectively reviewed. Results Patients’ median age was 8 years; 48% were female. Overall, 46% of patients had leukemia or lymphoma, 40% solid tumors, and 14% were HSCT recipients. Patients were neutropenic [absolute neutrophil count (ANC) <1000] during 70% of episodes and severely neutropenic (ANC <100) in 59%. The most common bacteria identified included E. coli (42%), Ps. aeruginosa (17%), and Klebsiella spp. (10%); 26% of episodes were polymicrobial and 24% of patients had focal infections complicating their bacteremia. Overall, 52% of episodes were caused by CEF-R organisms, including 57% of infections caused by E. coli. Demographic characteristics of CWC with infections caused by CEF-R organisms were similar to those with CEF-S organisms, except that these patients were more likely to have leukemia (adjusted OR 3.6, 95% CI 1.3–9.8) and to have had previous colonization or infection caused by a CEF-R organism (adjusted OR 14.4, 95% CI 2.7–76.0). CWC with infectious caused by CEF-R organisms were more likely to receive intensive care at admission and in the first 3 days of hospitalization than those with CEF-S isolates, but these differences were not statistically significant. The median time to administration of effective antimicrobial therapy was 0.53 hours for episodes caused by CEF-S bacteria and 12.05 hours for episodes caused by CEF-R organisms (P < 0.001), and CEF-R bacteremia was associated with increased time to microbiological resolution (P = 0.002) and a greater likelihood of early modification of treatment because of poor clinical response (5% vs. 14%, P = 0.043). CWC with CEF-R bacteremia had a longer median duration of fever (1 day vs. 2 days, P = 0.015), time to resolution of other signs and symptoms of infection (2 days vs. 4 days, P = 0.005), and median duration of hospitalization (6 vs. 11.5 days, P < 0.001) relative to CEF-S infections. All-cause mortality at hospital discharge and at 30 days was 8% in both CEF-S and CEF-R infections and was associated with the presence of relapsed or refractory malignancy and other significant medical comorbidities. Conclusion Over half of the episodes of GNB in this study were caused by CEF-R organisms. Infection with CEF-R organisms was associated with a delay in the administration of effective therapy and greater morbidity, but not greater mortality. Further studies are warranted to clarify the relationship between antimicrobial resistance, disease severity, treatment, and infection outcomes.

Effect of Obesity on Clinical Outcomes of Patients Treated With Cefepime.

Background: As the prevalence of obesity climbs, dosing of antimicrobials, particularly cephalosporins, is becoming a greater challenge for clinicians. Data are lacking for appropriate dosing of cefepime, an anti-pseudomonal cephalosporin that is widely used as an empiric anti-pseudomonal agent. Objective: The purpose of this study was to determine the rate of clinical treatment failure in obese patients compared with nonobese patients receiving cefepime as definitive monotherapy. Methods: Adult inpatients treated with cefepime monotherapy for ≥72 hours were included. Patients were excluded if they (1) were not able to achieve culture clearance within 72 hours and (2) had polymicrobial infections requiring more than one antibiotic for definitive therapy. Results: Fifty-eight obese patients and 56 nonobese patients were included. Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp were the most prevalent organisms isolated. Most organisms had a minimum inhibitory concentration of ≤1 µg/mL to cefepime with no differences in minimum inhibitory concentration distributions between groups. Definitively, 60% of patients received cefepime 1 g, while almost 40% received cefepime 2 g. Clinical failure occurred in 52% of patients (67% obese vs 36% nonobese; P = .001), with study group (odds ratio = 1.057, 95% confidence interval = 1.008-1.109) and respiratory source (odds ratio = 3.251, 95% confidence interval = 1.378-7.667) being independent predictors of failure. There were no differences in hospital length of stay, all-cause mortality, or 30-day readmissions. Conclusions: Obese patients treated with cefepime are more likely to experience treatment failure than nonobese patients. Larger trials examining the reasons for clinical failure in obese patients treated with cefepime are needed to confirm the findings from this preliminary work.

Cefepime Versus Cefepime Plus Amikacin as an Initial Antibiotic Choice for Pediatric Cancer Patients With Febrile Neutropenia in an Era of Increasing Cefepime Resistance.

We investigated the treatment outcomes before and after the addition of amikacin to cefepime monotherapy as an initial empirical antibiotic treatment in pediatric cancer patients with febrile neutropenia. This was a retrospective historical cohort study. The subjects were pediatric cancer patients who visited the emergency room at the Samsung Medical Center, Seoul, Korea, due to chemotherapy-induced febrile neutropenia, between January 2011 and December 2016. Since September 2014, the empirical antimicrobial treatment regimen for febrile neutropenia was changed from high-dose cefepime monotherapy to combination therapy of adding a single dose of amikacin. Two hundred twenty-five bacteremia episodes in 164 patients were reported during the study period. Bacteremia caused by cefepime-resistant Gram-negative bacteria was observed in 16% of patients before September 2014 and in 21% of the patients after September 2014 (P = 0.331). Use of appropriate empirical antibiotic treatments increased from 62% to 83% following addition of amikacin to cefepime treatment (P = 0.003). The duration of fever was shorter in the cefepime plus amikacin group than in the cefepime group (22 vs. 34 hours, P = 0.014); however, rates of septic shock and pediatric intensive care unit hospitalizations were not significantly different between the 2 groups (septic shock, both 7%, P = 0.436; pediatric intensive care unit 3% vs. 1%, P = 0.647). We observed no additional benefit of amikacin addition to high-dose cefepime monotherapy. Therefore, adding amikacin to cefepime monotherapy in conditions where cefepime-resistant Gram-negative bacteremia amounts to 20% or less may not be justified.

Outcomes of treating AmpC-producing Enterobacterales bacteraemia with carbapenems vs. non-carbapenems

IntroductionAmpC β-lactamases are found in Enterobacter species, Serratia species, Citrobacter freundii, Providencia species and Morganella morganii (‘ESCPM’). Carbapenems are commonly used to treat severe ‘ESCPM’ infections. Carbapenem-sparing agents are needed because of increasing carbapenem resistance worldwide. Use of cefepime and piperacillin-tazobactam has limited supportive clinical data. We evaluated the efficacy of non-carbapenems vs. carbapenems in ‘ESCPM’ bacteraemia. MethodsA retrospective cohort study was conducted on patients with ‘ESCPM’ bacteraemia. Primary outcome was 30-day mortality. Analyses were performed on patients who received carbapenems vs. piperacillin-tazobactam or cefepime monotherapy as empirical and definitive therapy. Propensity score for carbapenem therapy was adjusted for in multivariate analyses for 30-day mortality. ResultsA total of 241 patients were included. The most common bacterium isolated was Enterobacter species (58.1%). Common sources were urinary (22.8%) and vascular lines (22.0%). Carbapenems (28.6%) and piperacillin-tazobactam (28.6%) were the commonest empirical antibiotics. Carbapenems (54.8%) and cefepime (23.7%) were the most common definitive antibiotics. Median Pitt bacteraemia score was 1 (interquartile range [IQR], 0-2). Overall, 30-day mortality was 12.9%.Adjusted multivariate analyses for empirical and definitive antibiotic treatment models yielded risk factors for 30-day mortality, including higher Pitt bacteraemia score (empirical: adjusted OR [aOR] 1.21 for each point increase, 95% confidence interval [CI]:1.01-1.45; definitive: aOR 1.33 for each point increase, 95% CI:1.06-1.69) and age (empirical: aOR 1.04 for each year increase, 95% CI:1.01-1.08). Empirical piperacillin-tazobactam (aOR 0.29, 95% CI:0.07-1.27) and definitive cefepime (aOR 0.65, 95% CI:0.12-3.55) were not associated with 30-day mortality. ConclusionsCompared with carbapenem therapy, empirical piperacillin-tazobactam and definitive cefepime were not associated with 30-day mortality in ‘ESCPM’ bacteraemia.

Intraperitoneal Cefepime Monotherapy Versus Combination Therapy of Cefazolin Plus Ceftazidime for Empirical Treatment of CAPD-Associated Peritonitis: A Multicenter, Open-Label, Noninferiority, Randomized, Controlled Trial

Compared to combination therapy, intraperitoneal (IP) cefepime monotherapy for continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis may provide potential benefits in lowering staff burden, shortening time-consuming antibiotic preparation, and reducing bag contamination risk. This study sought to evaluate whether cefepime monotherapy is noninferior to combination regimens. Multicenter, open-label, noninferiority, randomized, controlled trial. Adult incident peritoneal dialysis (PD) patients with CAPD-associated peritonitis in 8 PD centers in Thailand. Random assignment to either IP monotherapy of cefepime, 1g/d, or IP combination of cefazolin and ceftazidime, 1g/d, both given as continuous dosing. Primary end point: resolution of peritonitis at day 10 (primary treatment response). initial response (day 5), complete cure (relapse/recurrence-free response 28 days after treatment completion), relapsing/recurrent peritonitis, and death from any cause. Noninferiority would be confirmed for the primary outcome if the lower margin of the 1-sided 95% CI was not less than-10% for difference in the primary response rate. A 2-sided 90% CI was used to demonstrate the upper or lower border of the 1-sided 95% CI. There were 144 eligible patients withCAPD-associated peritonitis, of whom 70 and74 patients were in the monotherapy andcombination-therapy groups, respectively. Baseline demographic and clinical characteristics were not different between the groups. The primary response was 82.6% in themonotherapy group and 81.1% in the combination-therapy group (treatment difference, 1.5%; 90% CI,-9.1% to 12.1%; P=0.04). There was no significant difference in the monotherapy group compared with the combination-therapy group in terms of initial response rate (65.7% vs 60.8%; treatment difference, 4.9%; 95% CI,-10.8% to 20.6%; P=0.5) and complete cure rate (80.0% vs 80.6%; treatment difference,-0.6%; 95% CI,-13.9% to 12.8%; P=0.7). Relapsing and recurrent peritonitis occurred in 4.6% and 4.6% of the monotherapy group and 4.2% and 5.6% of the combination-therapy group (P=0.9and P=0.8, respectively). There was nominally higher all-cause mortality in the monotherapy group (7.1% vs 2.7%; treatment difference, 4.4%; 95% CI,-2.6% to 11.5%), but this difference was not statistically significant (P = 0.2). Not double blind. IP cefepime monotherapy was noninferior to conventional combination therapy for resolution of CAPD-associated peritonitis at day 10 and may be a reasonable alternative first-line treatment. This study is supported by The Kidney Foundation of Thailand (R5879), Thailand; Rachadaphiseksompotch Fund (RA56/006) and Rachadaphicseksompotch Endorsement Fund (CU-GRS_61_06_30_01), Chulalongkorn University, Thailand; National Research Council of Thailand (156/2560), Thailand; and Thailand Research Foundation (IRG5780017), Thailand. Registered at ClinicalTrials.gov with study number NCT02872038.

Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia.

Beta lactams are standard empirical therapy for febrile neutropenia (FN). The aim of this study was to evaluate the efficacy and safety of cefepime monotherapy compared with cefoperazone/sulbactam plus amikacin (CS + A) for empirical treatment of high risk FN. One hundred seventy-five patients with 336 FN episodes were randomized to receive either cefepime (2g q8h for adults and 50mg/kg q8h for children) or CS (2g q8h for adults and 50mg/kg q8h for children) plus amikacin (15mg/kg once a day). Positive response was defined as afebrile within 72h of starting antibiotics, persistent afebrile status more than 48h and no requirement of second-line antibiotics and antifungal agents. Three hundred thirty-six episodes were assessable for efficacy (168 cefepime, 168 CS + A). The positive response to antibiotics was identical for cefepime (53%) and CS + A (53%). Positive response was similar in MDI (microbiologically documented infection), 50 vs. 35% (p = 0.248), CDI (clinically documented infection), 50 vs. 35% (p = 0.259), combination CDI + MDI, 25 vs. 15% (p = 0.400), FUO (fever of unknown origin), 68 vs. 72% (p = 0.577) respectively in the two groups. The successful discontinuation of antibiotics at 72h in FUO was similar in both groups (60 vs. 59%, p = 0.544). Total drug-related adverse events were similar in both groups (8 vs. 6%) except renal dysfunction was high in CS + A (1 vs. 7 events). Mortality was the same between two groups (8 vs 7%). Cefepime monotherapy and CS + A had similar efficacy as first-line therapy for FN. Discontinuation of empirical antibiotics is safe and feasible approach in selected group of FUO patients.

The Dose-Dependent Efficacy of Cefepime in the Empiric Management of Febrile Neutropenia: A Systematic Review and Meta-Analysis.

BackgroundDespite reports questioning its efficacy, cefepime remains a first-line option in febrile neutropenia. We aimed to re-evaluate the role of cefepime in this setting.MethodsWe searched the PubMed and EMBASE databases to identify randomized comparisons of (1) cefepime vs alternative monotherapy or (2) cefepime plus aminoglycoside vs alternative monotherapy plus aminoglycoside, published until November 28, 2016.ResultsThirty-two trials, reporting on 5724 patients, were included. Clinical efficacy was similar between study arms (P = .698), but overall mortality was greater among cefepime-treated patients (risk ratio [RR] = 1.321; 95% confidence interval [CI], 1.035–1.686; P = .025). Also of note, this effect seemed to stem from trials using low-dose (2 grams/12 hours, 100 mg/kg per day) cefepime monotherapy (RR = 1.682; 95% CI, 1.038–2.727; P = .035). Cefepime was also associated with increased mortality compared with carbapenems (RR = 1.668; 95% CI, 1.089–2.555; P = .019), a finding possibly influenced by cefepime dose, because carbapenems were compared with low-dose cefepime monotherapy in 5 of 9 trials. Treatment failure in clinically documented infections was also more frequent with cefepime (RR = 1.143; 95% CI, 1.004–1.300; P = .043). Toxicity-related treatment discontinuation was more common among patients that received high-dose cefepime (P = .026), whereas low-dose cefepime monotherapy resulted in fewer adverse events, compared with alternative monotherapy (P = .009).ConclusionsCefepime demonstrated increased mortality compared with carbapenems, reduced efficacy in clinically documented infections, and higher rates of toxicity-related treatment discontinuation. The impact of cefepime dosing on these outcomes is important, because low-dose regimens were associated with lower toxicity at the expense of higher mortality.

524PD Cefepime versus cefoperazone/sulbactum plus amikacin as empirical antibiotic therapy in cancer patients with febrile neutropenia

Background Cefepime is recommended first line therapy for patients with febrile neutropenia (FN). In view of rising incidence of resistance to 3rd generation cephalosporins at our center we aimed to compare the efficacy and safety of cefepime monotherapy with cefoperazone/sulbactum plus amikacin as empirical antibiotic in cancer patients with FN Methods In this prospective, open label, single-center study, high risk FN episodes in both adults and pediatric patients with hematological or solid malignancies were randomized to receive either cefoperozone/sulbactum (2 g every 8 h for adults and 150 mg/kg/day for pediatrics) plus Amikacin 20mg/kg every 24 hrs or cefepime (2 g every 8 h for adults and 150 mg/kg/day) intravenously. The primary outcome was positive response to study antibiotics (defervescence within 72 hrs, afebrile period continued for more than 48 hrs, no requirement for 2nd line antibiotcs). The secondary outcome was to study the effectiveness of discontinuation of empirical antibiotic at 72 hours in fever of unknown origin (FUO) and hemodynamically stable patients, irrespective of grade and duration of neutropenia Results For efficacy, 278 FN episodes were assessable (139 cefepime,139 cefoperozone/ sulbactum plus Amikacin). The microbiologically documented infection (MDI) rate was 27% (n = 75) in the entire cohort; Pseudomonas (12%), Klebsiella (6%), Acinetobacter (5%), E.Coli (2%). The positive response to antibiotics was similar in both groups (cefepime-55%, cefeperozone/sulbactum plus Amikacin-51%; p = 0.7) including in sub-group of MDI (37% and 38% respectively). The number of patients who had successful antibiotic discontinuation after 72 hrs was same in both groups [41% (n = 29) & 38.5% (n = 27) respectively] Mortality rate was 10% (14 in cefepime group and 13 patients in cefeperozone/sulbactum plus Amikacin group). Drug related adverse events were reported in 3% versus 7% respectively Conclusions The efficacy of cefepime monotherapy is equivalent to cefoperazone/ sulbactum plus amikacin in cancer patients with febrile neutropenia. Antibiotic discontinuation in FUO patients who become afebrile after 72 hrs is a safe and feasible approach Legal entity responsible for the study JIPMER Funding JIPMER, Pondicherry Disclosure All authors have declared no conflicts of interest.

A clinical evaluation of efficacy and safety of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia in a tertiary care centre of north India

To evaluate clinically the efficacy and safety in northern India of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia. Children aged ≤18 years admitted febrile with chemotherapy-induced neutropenia were randomised into two groups comprising 20 cases in each group viz. CEF (receiving cefepime only) and PIP-TAZO (receiving piperacillin-tazobactam). Based on clinical and laboratory tests, patients were classified into: microbiologically documented infections (MDI); clinically documented infections (CDI); and unexplained fever (UF). They were assessed for clinical signs and symptoms as well as laboratory parameters at the time of enrolment and subsequently on days 3 and 7. Incidence of MDI, CDI and UF were 22.5%, 47.5% and 30%, respectively. The mean duration of neutropenia (in days) was 5.45 ± 2.1 in the PIP-TAZO group and 5.5 ± 1.5 in the CEF group (P = 0.305). The success rate defined as clearing infection effectively and improvement of neutropenia was comparable (P = 0.705). There was a mortality rate of 20% in the PIP-TAZO group as compared to 10% in the CEF group. We conclude that cefepime monotherapy and piperacillin-tazobactam are equally efficacious and safe in treating patients with febrile neutropenia. Empirical monotherapy with cefepime would prevent an unnecessary extra economic burden as well as avoiding the serious adverse or toxic effects of multi-drug regimes, especially in low- and middle-income countries.

In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrug-resistant Gram-negative Enterobacteriaceae.

The combination of cefepime with AAI101, a novel extended-spectrum β-lactamase inhibitor, possesses potent in vitro activity against many resistant Gram-negative pathogens. Against a panel of 20 mostly carbapenemase-producing cefepime-nonsusceptible strains of the family Enterobacteriaceae, we evaluated the MICs of cefepime in the presence of various fixed AAI101 concentrations (1, 2, 4, 8, and 16 mg/liter) and the in vivo efficacy of simulated human doses of cefepime and cefepime-AAI101 in a neutropenic murine thigh infection model. At 2 h after inoculation, mice were dosed with regimens that provided a profile mimicking the free drug concentration-time profile observed in humans given cefepime at 2 g every 8 h (q8h; as a 30-min infusion) or cefepime-AAI101 at 2 g/0.5 g q8h (as a 30-min infusion). Efficacy was determined by calculation of the change in thigh bacterial density (log10 number of CFU) after 24 h relative to the starting inoculum (0 h). After 24 h, bacterial growth of 2.7 ± 0.1 log10 CFU (mean ± standard error) was observed in control animals. Efficacy for cefepime monotherapy was observed against only 3 isolates, whereas increases in bacterial density similar to that in the control animals were noted for the remaining 17 strains (all with cefepime MICs of ≥ 64 mg/liter). The humanized cefepime-AAI101 dosing regimen resulted in bacterial reductions of ≥ 0.5 log10 CFU for 12 of the 20 strains. Evaluation of efficacy as a function of the fraction of the dosing interval during which free drug concentrations were above the MIC determined with different fixed concentrations of AAI101 suggested that a fixed concentration of 8 mg/liter AAI101 is most predictive of in vivo activity for the studied regimen.

Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia

Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration (fCmin) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CLCr), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with clinical failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CLCr and cefepime Cmin in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the Cmin predicted by the pharmacokinetic model was 5.8mg/L using a CLCr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced clinical failure. CART analysis determined patients with an fCmin/MIC≥2.1 had a significantly lower risk of clinical failure (OR=0.11, 95% CI 0.02–0.67; P=0.017). The fCmin/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fCmin/MIC in therapeutic drug monitoring should be further explored.

Cefepime monotherapy for febrile neutropenia in patients with lung cancer

We assessed the efficacy and safety of cefepime monotherapy (1 g intravenously every 8 h) for febrile neutropenia in patients with lung cancer in a multi-institutional phase II study. Patients treated with chemotherapy with or without radiotherapy for lung cancer were eligible for this study. Other eligibility criteria included fever (temperature of ≥38.0 °C) and an absolute neutrophil count of <500/mm(3) or <1000/mm(3) with an expected decline to <500/mm(3) within the next 48 h. Risk assessment was performed using the Multinational Association of Supportive Care in Cancer risk-index score. Cefepime 1 g was given intravenously every 8 h. The primary endpoint was the response rate at the end of cefepime therapy. Co-administration of granulocyte-colony-stimulating factor was permitted. Of 54 patients enrolled, 39 were classified in the low-risk group and 15 in the high-risk group. Overall response rate was 78% (95% CI: 64.4-88.0%). The response rates were 85% (95% CI: 69.5-94.1%) in the low-risk group and 60% (95% CI: 32.3-83.7%) in the high-risk group, respectively. One patient died from septic shock due to Enterobacter cloacae bacteremia. There was no significant adverse event. Cefepime 1 g intravenously every 8 h appears to be effective for febrile neutropenia in patients with lung cancer, especially in those with low-risk febrile neutropenia, and is well tolerated. UMIN Clinical Trials Registry, UMIN000006157.

Meta-analysis of efficacy and safety of cefepime

In this issue of The Journal, Adderson et al report a systematic review and meta-analysis of randomized controlled trials of the fourth generation cephalosporin agent, cefepime, in children following the Food and Drug Administration's review of the report of increased all-cause mortality with cefepime monotherapy versus comparator in a meta-analysis predominantly involving adults. The meta-analysis of pediatric patients by Adderson et al does not support excess all-cause mortality or clinical failure associated with cefepime therapy in trials.

Cefepime: A Review of Its Use in the Treatment of Serious Bacterial Infections

Serious bacterial infections with their high bioburden are often difficult to treat. Emergence of drug-resistant bacteria has worsened the situation, and management of these cases has become a therapeutic challenge. Prompt institution of appropriate antibiotic is vital in order to decrease complications and fatalities. Cefepime is a new fourth generation parenteral cephalosporin which holds promise for management of these severe infections. It has been shown to be useful in critical pneumonias, soft and bone tissue infections, urinary tract infections and febrile neutropenia. It eradicates organisms which have shown resistance to other β-lactam antibiotics. It is stable to hydrolysis by the common plasmid and chromosomally mediated β-lactamases. The twice daily dosing and improved efficacy even at low dosage makes it a suitable alternative to ceftazidime and carbapenems. It is well tolerated by all age groups and is safe even for newborns. Cefepime monotherapy gives both a good clinical response and an excellent microbiological clearance. In order to preserve its anti-bacterial potency, prudent use of cefepime is warranted. Research into its efficacy and safety with other β-lactamase inhibitors is ongoing and will benefit mankind.

Piperacillin/tazobactam versus cefepime for the empirical treatment of pediatric cancer patients with neutropenia and fever: A randomized and open‐label study

This is a prospective, randomized, and open-label clinical trial that examines the efficiency and safety of PIP/TAZO monotherapy in comparison to cefepime (CEF), for the empirical treatment of pediatric cancer patients with neutropenia and fever. One hundred thirty-one consecutive febrile episodes in 70 neutropenic pediatric cancer patients received randomized treatment either with piperacillin/tazobactam (PIP/TAZO) 80 mg/kg piperacillin/10 mg/kg tazobactam every 6 hr or CEF 50 mg/kg every 8 hr. Clinical response was determined at completion of therapy. Duration of fever, neutropenia, hospitalization, the need for modification of the therapy, and mortality rates were compared between the two groups. One hundred twenty-seven episodes in 69 patients (35 females, 34 males) with a median age of 4.2 years were assessed for efficiency (65 PIP/TAZO, 62 CEF). The frequency of success without modification of treatment was nearly identical for both PIP/TAZO (60.0%) and CEF (61.3%) (P > 0.05). The overall response rate, with or without modification of assigned treatment, was 96.9% for PIP/TAZO and 98.4% for CEP (P > 0.05). Infection-related mortality at the end of the febrile episode was 2.4%. Duration of fever and hospitalization were not different between the treatment groups. No major side effects were observed in neither of the groups. PIP/TAZO treatment was as effective and safe as CEF monotherapy as an initial empirical regimen in pediatric cancer patients with fever and neutropenia.

Cefepime Monotherapy is as Effective as Ceftriaxone Plus Amikacin in Pediatric Patients with Cancer and High-Risk Febrile Neutropenia: A Randomized Comparison

The empirical use of antibiotic therapies is widely accepted in patients with fever and neutropenia during cancer chemotherapy. The use of intravenous monotherapy with broad-spectrum antibiotics in patients with high-risk of complications is an appropriate alternative. However, few data are available in pediatric patients. We conducted a prospective, randomized, open study in patients with lymphoma or leukemia who had fever and neutropenia during chemotherapy. Patients were randomized to receive cefepime (CFP) or ceftriaxone plus amikacin (CFT+AK). A total of 57 patients with 125 episodes of fever and neutropenia were evaluated (CFP, 62 and CFT + AK, 63 episodes). The mean neutrophil count at admission was 118.6 cells mm-3 (CFP) and 107 cells mm-3 (CFT+AK). The mean duration of neutropenia was 9.0 days (CFP) and 8.0 days (CFT+AK). Analyzing only the first episodes of each patient, CFP treatment was successful in 65.5% of the episodes and CFT+AK were successful in 64.3%. Overall rates of success with modification were 90% (CFP) and 89% (CFT+AK). No major treatment-emergent toxicity was reported. Monotherapy with CFP seems to be as effective and safe as the combination of CFT+AK for initial empirical therapy in children and adolescents with NF.

Efficacy and safety of cefepime in late-onset ventilator-associated pneumonia in infants: a pilot randomized and controlled study

Multidrug-resistant organisms cause late-onset ventilator-associated pneumonia (VAP). In a pilot, randomized and controlled study, the efficacy and safety of cefepime, in late-onset VAP in infants, have now been evaluated in Malaysia. Thirty children aged <1 year with late-onset VAP (i.e. VAP occurring 5 or more days after intubation) were randomized to receive cefepime or, as a control, ceftazidime. The clinical responses and the microbiological clearance of tracheal aspirates were evaluated in each arm. Adverse events, if any, were monitored clinically and by blood tests. Ten of the 15 children given cefepime and five of the 15 given ceftazidime showed a satisfactory clinical response (P<0.1). Cefepime appeared significantly better at clearing polymicrobial infections from tracheal aspirates. There were no fatalities in the cefepime arm but three in ceftazidime (P<0.1). The mean (S.E.) durations of antibiotic use were 9.4 (1.5) days for cefepime and 7.6 (1.0) days for ceftazidime (P>0.05). No serious adverse effects were observed in either arm. In conclusion, in late-onset VAP in infants, cefepime monotherapy appears to be at least as effective and safe as ceftazidime monotherapy, with better microbiological clearance.

Randomized Study of Cefepime versus Ceftazidime plus Amikacin in Patients with Solid Tumors Treated with High Dose Chemotherapy (HDC) and Peripheral Blood Stem Cell Support (PBSCS) with Febrile Neutropenia

This randomized clinical trial evaluated the efficacy and safety of monotherapy with cefepime for patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia. Patients with solid tumors treated with HDC and PBSCS, that developed fever and neutropenia (absolute neutrophil count < 500 cells/microL) were eligible, and randomly assigned to receive ceftazidime plus amikacin or cefepime. Fifty-one episodes were randomized, and all were evaluable (27 received ceftazidime plus amikacin arm, and 24 cefepime). Major efficacy endpoints did not show significant differences, with success rates of 44.4% and 54.2% (p = 0.481) for the combination arm and the monotherapy arm, respectively. The proportion of patients that became afebrile in the first 24 hours was significantly higher in the cefepime group (41.7% vs 11.1%, respectively; p = 0.012). However, due to its premature closure and small sample size, this study lacks the adequate power to definitely address this question. Cefepime monotherapy appeared to have an equivalent efficacy and safety as empiric treatment in febrile neutropenia episodes in a highrisk population compared with ceftazidime and amikacin. Nevertheless, this study is not adequately powered to answer this question. Given the small number of patients randomized and the single-center nature of this study, these results must be cautiously interpreted.